PROJECT SUMMARY Traumatic brain injury (TBI) is a severe disabling neurological disorder that affects more than 1.7 million Americans each year. Available treatments are only aimed at stabilizing an individual with TBI and consequently there is a great need for development of new therapeutic strategies. All-trans retinoic acid (atRA) is an important endogenous signaling molecule. Recent data show that atRA plays an important role in maintaining neuronal plasticity, learning and memory, increasing trauma-induced neurogenesis and decreasing glial activation in human or in animal, and support our hypothesis that increasing atRA in the brain will improve recovery of TBI victims. However, atRA has poor pharmacokinetics and it induces its own clearance resulting in loss of activity during long-term treatment. The clearance of RA is predominantly mediated by cytochrome P450 family 26 enzymes (CYP26). The CYP26 family has three isoforms: CYP26A1, CYP26B1 and CYP26C1. CYP26B1 appears to be the predominant brain isoform. We hypothesize that selective inhibition of CYP26B1 in the brain will increase neuronal atRA concentrations and will treat memory impairment and neuroinflammation associated with TBI, providing a therapeutic advantage for TBI victims. We designed an approach that led to the identification of a novel class of selective nanomolar CYP26B1 inhibitors. Such novel class of compounds is expected to be specific for CYP26B1 isoform avoiding non-target P450 inhibition associated with previously described azole-based CYP26 inhibitors. The objective of this proposal is to optimize our novel selective inhibitors of CYP26B1, to increase atRA concentration in the brain and treat memory impairment and neuroinflammation associated with TBI. Using our previously discovered lead structures, we propose to first generate a series of new compounds with improved CYP26B1 inhibition potency and selectivity using X-ray crystallography and computer-guided chemical modifications. In the second part of the proposal, we will demonstrate that CYP26B1 inhibition result in an improvement of memory deficit and reduce neuroinflammation and glial activation in a rat model of TBI. RELEVANCE We propose an innovative new therapeutic strategy to treat Traumatic brain injury (TBI) with CYP26B1 inhibitors that will increase neuronal retinoic acid concentration. We detail a plan to validate this target by optimizing our previously discovered CYP26B1 inhibitors for evaluation in animal models of TBI. If successful, this study could provide a novel therapeutic approach for the treatment of TBI.